Inhibition of tumor suppressor p73 by nerve growth factor receptor via chaperone-mediated autophagy

The tumor suppressr p73 is a homolog of p53 and is capable of inducing cell cycle arrest and apoptosis. Here, we identify nerve growth factor receptor (NGFR, p75NTR, or CD271) as a novel negative p73 regulator. p73 activates NGFR transcription, which, in turn, promotes p73 degradation in a negative feedback loop. NGFR directly binds to p73 central DNA-binding domain and suppresses p73 transcriptional activity as well as p73-mediated apoptosis in cancer cells. Surprisingly, we uncover a previously unknown mechanism of NGFR-facilitated p73 degradation through the chaperone-mediated autophagy (CMA) pathway. Collectively, our studies demonstrate a new oncogenic function for NGFR in inactivating p73 activity by promoting its degradation through the CMA.